Exposure to and Biomarker Responses From Legacy and Emerging Contaminants Along Three Drainages in the Milwaukee Estuary, Wisconsin, USA.

Legacy contaminants and contaminants of emerging concern (CECs) were assessed in tree swallow (Tachycineta bicolor) tissue and diet samples from three drainages in the Milwaukee estuary, Wisconsin, USA, to understand exposures and possible biomarker responses. Two remote Wisconsin lakes were assessed for comparative purposes. Bioaccumulative classes of contaminants, such as polybrominated diphenyl ethers and per- and polyfluoroalkyl substances, while at higher concentrations than the reference lakes, did not vary significantly among sites or among the three drainages. Polycyclic aromatic hydrocarbons were assessed in diet and sediment and were from primarily pyrogenic sources. Ten biomarkers were assessed relative to contaminant exposure. Polychlorinated biphenyls (PCBs) were elevated above reference conditions at all Milwaukee sites but did not correlate with any measured biomarker responses. Only one site, Cedarburg, just downstream from a Superfund site, had elevated PCBs compared to other sites in the Milwaukee estuary. Few non-organochlorine insecticides or herbicides were detected in tree swallow liver tissue, except for the atrazine metabolite desethylatrazine. Few pharmaceuticals and personal care products were detected in liver tissue except for N,N-diethyl-meta-toluamide, iopamidol, and two antibiotics. The present study is one of the most comprehensive assessments to date, along with the previously published Maumee River data, on the exposure and effects of a wide variety of CECs in birds. Environ Toxicol Chem 2024;43:856-877. © 2024 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Arsenic in drinking water and lung cancer: A systematic review of 35 years of evidence.

The association between higher arsenic concentrations in drinking water and lung cancer is well-established. However, the risk associated with lower levels of arsenic exposure remains uncertain. This systematic review and meta-analysis summarizes the evidence on the relationship between exposure to arsenic in drinking water and lung cancer outcomes as measured over a broad range of exposures, including lower levels. A total of 51 studies were included in the review and 15 met criteria for inclusion in meta-analysis. Risk estimates for lung cancer incidence and mortality were pooled and analyzed separately using Bayesian hierarchical random-effects models with a Gaussian observation submodel for log(Risk), computed using the "brms" R package. For lung cancer incidence, the predicted posterior mean relative risks (RRs) at arsenic concentrations of 10, 50 and 150 µg/L were 1.11 (0.86-1.43), 1.67 (1.27-2.17) and 2.21 (1.61-3.02), respectively, with posterior probabilities of 79%, 100% and 100%, respectively, for the RRs to be >1. The posterior mean mortality ratios at 20, 50 and 150 µg/L were 1.22 (0.83-1.78), 2.10 (1.62-2.71) and 2.41 (1.88-3.08), respectively, with posterior probabilities being above 80%. In addition to observing the dose-response relationship, these findings demonstrate that individuals exposed to low to moderate levels of arsenic (<150 µg/L) were at an elevated risk of developing or dying from lung cancer. Given the widespread exposure to lower levels of arsenic, there is an urgent need for vigilance and potential revisions to regulatory guidelines to protect people from the cancer risks associated with arsenic exposure.

Proteomic Profiling of Advanced Melanoma Patients to Predict Therapeutic Response to Anti-PD-1 Therapy.

PURPOSE: Despite high clinical need, there are no biomarkers that accurately predict the response of patients with metastatic melanoma to anti-PD-1 therapy. EXPERIMENTAL DESIGN: In this multicenter study, we applied protein depletion and enrichment methods prior to various proteomic techniques to analyze a serum discovery cohort (n = 56) and three independent serum validation cohorts (n = 80, n = 12, n = 17). Further validation analyses by literature and survival analysis followed. RESULTS: We identified several significantly regulated proteins as well as biological processes such as neutrophil degranulation, cell-substrate adhesion, and extracellular matrix organization. Analysis of the three independent serum validation cohorts confirmed the significant differences between responders (R) and nonresponders (NR) observed in the initial discovery cohort. In addition, literature-based validation highlighted 30 markers overlapping with previously published signatures. Survival analysis using the TCGA database showed that overexpression of 17 of the markers we identified correlated with lower overall survival in patients with melanoma. CONCLUSIONS: Ultimately, this multilayered serum analysis led to a potential marker signature with 10 key markers significantly altered in at least two independent serum cohorts: CRP, LYVE1, SAA2, C1RL, CFHR3, LBP, LDHB, S100A8, S100A9, and SAA1, which will serve as the basis for further investigation. In addition to patient serum, we analyzed primary melanoma tumor cells from NR and found a potential marker signature with four key markers: LAMC1, PXDN, SERPINE1, and VCAN.

Fertilization benefits the facultative parasitic plant Rhamphicarpa fistulosa while gains by the infected host Oryza sativa are marginalized.

BACKGROUND AND AIMS: Rhamphicarpa fistulosa (Hochst.) Benth. is an annual facultative parasitic plant adapted to hydromorphic soils. In sub-Saharan Africa it causes high crop losses as a weed in rainfed lowland rice (Oryza sativa L.). Fertilisers are often proposed as control measure against hemiparasitic weeds but understanding of nutrient effects on R. fistulosa is currently still elusive. METHODS: In two greenhouse pot experiments, conducted in 2016 in the Netherlands and in 2019 in the UK, host plants (O. sativa, cv IR64) and parasitic plants (R. fistulosa) were grown alone or combined, and subjected to different nutrient availability levels. Biomass measurements were used to assess if and how nutrient availability effects are expressed in the host and parasite. KEY RESULTS: Compared to parasite-free host plants, the biomass of parasite-infested plants was severely reduced and nutrient effects on host plant biomass were less pronounced. Inversely, increased nutrient availability did not have an effect on parasitic plants when grown alone, but when grown with a host the parasitic plant biomass proportionally increased. Grown together, the combined biomass of host plant and parasite was substantially lower than that of the host plant grown alone. The ratio in biomass between host plant and parasite was unaffected by nutrient availability. CONCLUSIONS: Fertilization benefits to rice plants are severely reduced but not completely nullified by R. fistulosa infection. The parasite's production and reproduction benefits accrued from increased nutrient availability are restricted to conditions in presence of a host plant. Host presence and nutrient effects are thus observed to be synergetic; R. fistulosa plants parasitizing a suitable host respond strongly to increasing levels of nutrients. This is associated with an increased root biomass of the parasitic plant itself but more likely resulting from exploitation of the nutrient uptake capacity of the host plant it parasitizes on.

Decoding information about cognitive health from the brainwaves of sleep.

Sleep electroencephalogram (EEG) signals likely encode brain health information that may identify individuals at high risk for age-related brain diseases. Here, we evaluate the correlation of a previously proposed brain age biomarker, the "brain age index" (BAI), with cognitive test scores and use machine learning to develop and validate a series of new sleep EEG-based indices, termed "sleep cognitive indices" (SCIs), that are directly optimized to correlate with specific cognitive scores. Three overarching cognitive processes were examined: total, fluid (a measure of cognitive processes involved in reasoning-based problem solving and susceptible to aging and neuropathology), and crystallized cognition (a measure of cognitive processes involved in applying acquired knowledge toward problem-solving). We show that SCI decoded information about total cognition (Pearson's r = 0.37) and fluid cognition (Pearson's r = 0.56), while BAI correlated only with crystallized cognition (Pearson's r = - 0.25). Overall, these sleep EEG-derived biomarkers may provide accessible and clinically meaningful indicators of neurocognitive health.

Small area disease mapping of cancer incidence in British Columbia using Bayesian spatial models and the smallareamapp R Package.

Introduction: There is an increasing interest in small area analyses in cancer surveillance; however, technical capacity is limited and accessible analytical approaches remain to be determined. This study demonstrates an accessible approach for small area cancer risk estimation using Bayesian hierarchical models and data visualization through the smallareamapp R package. Materials and methods: Incident lung (N = 26,448), female breast (N = 28,466), cervical (N = 1,478), and colorectal (N = 25,457) cancers diagnosed among British Columbia (BC) residents between 2011 and 2018 were obtained from the BC Cancer Registry. Indirect age-standardization was used to derive age-adjusted expected counts and standardized incidence ratios (SIRs) relative to provincial rates. Moran's I was used to assess the strength and direction of spatial autocorrelation. A modified Besag, York and Mollie model (BYM2) was used for model incidence counts to calculate posterior median relative risks (RR) by Community Health Service Areas (CHSA; N = 218), adjusting for spatial dependencies. Integrated Nested Laplace Approximation (INLA) was used for Bayesian model implementation. Areas with exceedance probabilities (above a threshold RR = 1.1) greater or equal to 80% were considered to have an elevated risk. The posterior median and 95% credible intervals (CrI) for the spatially structured effect were reported. Predictive posterior checks were conducted through predictive integral transformation values and observed versus fitted values. Results: The proportion of variance in the RR explained by a spatial effect ranged from 4.4% (male colorectal) to 19.2% (female breast). Lung cancer showed the greatest number of CHSAs with elevated risk (Nwomen = 50/218, Nmen = 44/218), representing 2357 total excess cases. The largest lung cancer RRs were 1.67 (95% CrI = 1.06-2.50; exceedance probability = 96%; cases = 13) among women and 2.49 (95% CrI = 2.14-2.88; exceedance probability = 100%; cases = 174) among men. Areas with small population sizes and extreme SIRs were generally smoothed towards the null (RR = 1.0). Discussion: We present a ready-to-use approach for small area cancer risk estimation and disease mapping using BYM2 and exceedance probabilities. We developed the smallareamapp R package, which provides a user-friendly interface through an R-Shiny application, for epidemiologists and surveillance experts to examine geographic variation in risk. These methods and tools can be used to estimate risk, generate hypotheses, and examine ecologic associations while adjusting for spatial dependency.

Lifetime cannabis exposure and small airway function in a population-based cohort study.

Background and objective: The long-term effects of cannabis on small airway function remain unclear. We investigated associations between cannabis use and small airway function in a general population sample. Methods: Cannabis use was ascertained at multiple ages from age 18 to 45 years and quantified as joint-years among 895 participants in the Dunedin Multidisciplinary Health and Development Study. Small airway function at ages 38 and 45 years was measured using impulse oscillometry (IOS) before and after inhalation of salbutamol. Analyses used multiple linear regression adjusting for tobacco use, body mass index and height. Longitudinal analyses of cannabis use between 38 and 45 years also adjusted for IOS at age 38 years. Results: Associations between lifetime cannabis joint-years and IOS differed between men and women: in women, cannabis use was associated with pre-bronchodilator resistance at 5 Hz (R 5) and 20 Hz (R 20), reactance at 5 Hz, area of reactance and resonant frequency, and marginally associated with the difference between R 5 and R 20. Cannabis use was only statistically significantly associated with pre-bronchodilator resonant frequency in men. Cannabis use between the ages of 38 and 45 years was associated with a similar pattern of changes in IOS measures. After salbutamol, cannabis use was only statistically significantly associated with R 5 and R 20 among women and none of the IOS measures among men. Conclusions: Cannabis use is associated with small airway dysfunction at age 45 years, indicating an increase in peripheral airway resistance and reactance. These associations were greater and mostly only statistically significant among women. Associations were weaker and mostly nonsignificant after bronchodilator use, suggesting that cannabis-induced changes in small airways may be at least partially reversible.

Improved Survival Prediction by Combining Radiological Imaging and S-100B Levels Into a Multivariate Model in Metastatic Melanoma Patients Treated With Immune Checkpoint Inhibition.

Purpose: We explored imaging and blood bio-markers for survival prediction in a cohort of patients with metastatic melanoma treated with immune checkpoint inhibition. Materials and Methods: 94 consecutive metastatic melanoma patients treated with immune checkpoint inhibition were included into this study. PET/CT imaging was available at baseline (Tp0), 3 months (Tp1) and 6 months (Tp2) after start of immunotherapy. Radiological response at Tp2 was evaluated using iRECIST. Total tumor burden (TB) at each time-point was measured and relative change of TB compared to baseline was calculated. LDH, CRP and S-100B were also analyzed. Cox proportional hazards model and logistic regression were used for survival analysis. Results: iRECIST at Tp2 was significantly associated with overall survival (OS) with C-index=0.68. TB at baseline was not associated with OS, whereas TB at Tp1 and Tp2 provided similar predictive power with C-index of 0.67 and 0.71, respectively. Appearance of new metastatic lesions during follow-up was an independent prognostic factor (C-index=0.73). Elevated LDH and S-100B ratios at Tp2 were significantly associated with worse OS: C-index=0.73 for LDH and 0.73 for S-100B. Correlation of LDH with TB was weak (r=0.34). A multivariate model including TB change, S-100B, and appearance of new lesions showed the best predictive performance with C-index=0.83. Conclusion: Our analysis shows only a weak correlation between LDH and TB. Additionally, baseline TB was not a prognostic factor in our cohort. A multivariate model combining early blood and imaging biomarkers achieved the best predictive power with regard to survival, outperforming iRECIST.

Evaluation of Adiposity and Cognitive Function in Adults.

Importance: Excess adipose tissue increases other cardiovascular risk factors, which may be associated with vascular brain injury and cognitive impairment. However, the extent to which the amount and distribution of adipose tissue may be associated with lower cognitive scores, independent of its association with cardiovascular risk factors, is not well characterized. Objective: To investigate the association of adiposity on vascular brain injury and cognitive scores. Design, Setting, and Participants: A total of 9189 participants from the Canadian Alliance for Healthy Hearts and Minds (CAHHM) and the Prospective Urban Rural Epidemiological-Mind (PURE-MIND) cohort studies were included in this cross-sectional analysis. Of these adults, 9166 underwent bioelectrical impedance analysis to assess body fat (BF) percentage, and 6773 underwent magnetic resonance imaging to assess vascular brain injury and measure visceral adipose tissue (VAT) volume. Participants from CAHHM were recruited from January 1, 2014, to December 31, 2018, and PURE-MIND participants were recruited from January 1, 2010, to December 31, 2018. Both CAHHM and PURE-MIND comprise multisite, population-based cohorts. Participants from CAHHM are from Canada, and PURE-MIND participants are from Canada or Poland. Data analysis was performed from May 3 to November 24, 2021. Exposures: The percentage of BF and VAT were modeled as sex-specific quartiles. Vascular brain injury was defined as high white matter hyperintensities or silent brain infarction. Multivariable mixed models were used to examine factors associated with reduced cognitive scores. Main Outcomes and Measures: Cognitive function was assessed using the Digital Symbol Substitution Test (DSST; scores range from 0 to 133, with lower scores indicating lower cognitive function) and Montreal Cognitive Assessment (scores range from 0 to 30, with a score of ≥26 denoting normal cognitive function). Reduced cognition was defined as a DSST score less than 1 SD below the mean. Cardiovascular risk was assessed using the INTERHEART Risk Score (IHRS; scores range from 0 to 48; low risk is defined as a score of 0 to 9, moderate risk as 10 to 16, and high risk as 17 or higher). Results: A total of 9189 adults (mean [SD] age, 57.8 [8.8] years; 5179 [56.4%] women; and 1013 [11.0%] East and Southeast Asian; 295 [3.2%] South Asian; 7702 [83.8%] White European; and 179 [1.9%] other, including Black, Indigenous, mixed, and unknown ethnicity) participated in the study. Visceral adipose tissue was highly correlated with body adiposity measured by BF percentage (r = 0.76 in women; r = 0.70 in men). Cardiovascular risk factors increased with increasing BF percentage with the fourth quartile IHRS at 13.8 (95% CI, 13.5-14.0; P < .001 for trend) and with VAT with the fourth quartile IHRS at 13.3 (95% CI, 13.0-13.5; P < .001 for trend). Vascular brain injury increased with increasing BF percentage with the fourth quartile value at 8.6% (95% CI, 7.5%-9.8%; P = .007 for trend) and with increasing VAT with fourth quartile value at 7.2% (95% CI, 6.0-8.4; P = .05 for trend). Cognitive scores were lower with increasing BF percentage with the fourth quartile score of 70.9 (95% CI, 70.4-71.5; P < .001 for trend) and for VAT with the fourth quartile score of 72.8 (95% CI, 72.1-73.4; P < .001 for trend). For every 1-SD increase in BF percentage (9.2%) or VAT (36 mL), the DSST score was lower by 0.8 points (95% CI, 0.4-1.1; P < .001) for BF percentage and lower by 0.8 points (95% CI, 0.4-1.2; P < .001) for VAT, adjusted for cardiovascular risk factors and vascular brain injury. The population attributable risk for reduced DSST score for higher BF percentage was 20.5% (95% CI, 7.0%-33.2%) and for VAT was 19.6% (95% CI, 2.0%-36.0%). Higher BF percentage and VAT were not associated with Montreal Cognitive Assessment scores. Conclusions and Relevance: In this cross-sectional study, generalized and visceral adiposity were associated with reduced cognitive scores, after adjustment for cardiovascular risk factors, educational level, and vascular brain injury. These results suggest that strategies to prevent or reduce adiposity may preserve cognitive function.

Optimal spindle detection parameters for predicting cognitive performance.

STUDY OBJECTIVES: Alterations in sleep spindles have been linked to cognitive impairment. This finding has contributed to a growing interest in identifying sleep-based biomarkers of cognition and neurodegeneration, including sleep spindles. However, flexibility surrounding spindle definitions and algorithm parameter settings present a methodological challenge. The aim of this study was to characterize how spindle detection parameter settings influence the association between spindle features and cognition and to identify parameters with the strongest association with cognition. METHODS: Adult patients (n = 167, 49 ± 18 years) completed the NIH Toolbox Cognition Battery after undergoing overnight diagnostic polysomnography recordings for suspected sleep disorders. We explored 1000 combinations across seven parameters in Luna, an open-source spindle detector, and used four features of detected spindles (amplitude, density, duration, and peak frequency) to fit linear multiple regression models to predict cognitive scores. RESULTS: Spindle features (amplitude, density, duration, and mean frequency) were associated with the ability to predict raw fluid cognition scores (r = 0.503) and age-adjusted fluid cognition scores (r = 0.315) with the best spindle parameters. Fast spindle features generally showed better performance relative to slow spindle features. Spindle features weakly predicted total cognition and poorly predicted crystallized cognition regardless of parameter settings. CONCLUSIONS: Our exploration of spindle detection parameters identified optimal parameters for studies of fluid cognition and revealed the role of parameter interactions for both slow and fast spindles. Our findings support sleep spindles as a sleep-based biomarker of fluid cognition.

A bibliometric analysis of the top 100 most-cited case reports and case series in Endodontic journals.

AIM: To identify the top 100 most-cited case reports and case series published in Endodontic journals and to analyse their bibliometric characteristics. METHODOLOGY: The Clarivate Analytics' Web of Science (WoS), Scopus and PubMed databases were used to identify the top 100 most-cited case reports and case series in Endodontic journals. Complete bibliographic records of the selected case reports and case series were exported in plain text or BibTeX format and imported into the R environment for statistical computing and graphics. The following parameters were then analysed: names and affiliations of the authors, title, year of publication, journal of publication, first author, corresponding author, literature cited within reports, language, citation counts, impact factor of the journal, keywords, Keywords Plus and research topic. RESULTS: In total, 88 case reports and 12 case series published in English between 1977 and 2016 were identified as the most-cited reports in the field of Endodontics. The terms "case report(s)" or "case series" were not included in the title of 57 articles. The number of authors per report ranged from one to seven, with the average number of co-authors per report being 3.14. The most-cited author was M Trope (University of Pennsylvania, USA). The University of Washington and Private Practice, Cetraro, Italy, were the most productive institutions. The country whose case reports received the largest total number of citations was the United States. The largest number of the most-cited reports appeared in 2002, 2004 and 2007 (n = 7, respectively). According to the WoS database, the total number of citations ranged from 42 to 453, with the average number of citations per report being 79.97. The majority of the top 100 most-cited articles were published in the Journal of Endodontics and the International Endodontic Journal. The most frequently used author keywords were revascularization and mineral trioxide aggregate. The majority of the case reports and case series dealt with topics related to pulp regeneration. CONCLUSION: This bibliometric study provides a comprehensive overview on the progress, trends and current directions in clinical practice within the field of Endodontics.

Efficacy and safety of colchicine in inflammatory skin diseases: a retrospective, monocentric study in a large tertiary center.

Introduction: Colchicine is an ancient, but rarely used drug. Little data exist on its efficacy and safety in patients suffering from skin diseases. The objective of our study was to determine whether colchicine showed favorable efficacy and safety in our patients during the last 20 years.Methods: The hospital database was searched for patients treated with colchicine in the last 20 years (January 1, 1998 to December 31, 2017). Overall, total of 41 patients were included in our study.Results: In 63.4% of all patients, either a complete response or an improvement of disease was observed. Adverse events occurred rarely.Discussion: Colchicine is an effective and safe treatment.

Long-Term Disease Control After Allogeneic Hematopoietic Stem Cell Transplantation in Primary Cutaneous T-Cell Lymphoma; Results From a Single Institution Analysis.

Background: Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been proposed as curative approach for advanced cutaneous T-cell lymphomas (CTCL). Currently, there is no established consensus for the management of disease relapse after alloHSCT. Results: Ten patients, previously treated with multiple lines of systemic treatment, received alloHSCT. Six patients had achieved partial response (PR, N = 5) and complete response (CR, N = 1) prior to HSCT. Post-HSCT, seven patients (N = 7) relapsed after a median time of 3.3 months (0.5-7.4 months) and were subsequently treated with radiotherapy (RT, N = 1), RT and adoptive T-cell transfer with EBV specific cells (N = 1), R-CHOP (N = 1) and interferon alpha-2a combined either with donor lymphocyte infusion (N = 1) or with brentuximab-vedotin (N = 1). One patient (N = 1) achieved PR only after reducing the immunosuppression. Two patients relapsed again and received interferon alpha-2a and brentuximab-vedotin, respectively. After a median follow-up time of 12.6 months (3.5-73.7 months) six patients were alive (60%) and four had deceased, three (N = 3) due to CTCL and one (N = 1) due to GVHD. Conclusion: Disease relapse after alloHSCT can be controlled with available treatments. For most patients who ultimately relapsed, reduction of immunosuppression and interferon alpha-2a either administered alone or in combination with another systemic agent were preferred. Although interferon alpha-2a, similarly to immunosuppression reduction, may be beneficial for the achievement of graft-vs.-lymphoma effect, the risk of simultaneous worsening of GVHD must be carefully evaluated and taken into consideration.

Citation Classics on Dental Caries: A Systematic Review.

OBJECTIVE: A systematic search was performed for the identification and analysis of the 100 most often cited articles on dental caries and to highlight the changing trends in the field of dentistry over time. MATERIALS AND METHODS: The search was performed without any restriction on the study design, publication year, or language using the Web of Science (WoS) group of Clarivate Analytics enabling the search through "All Databases." Based on the citation count as available in WoS, the articles were sorted in a descending manner. Information regarding each article was then extracted, which included its authorship, counts of citation (in other databases), citation density, current citation index (2019), publication year, country of publication, journal of article, evidence level based on study design, and keywords description. RESULTS: The count of citation for each article varied in each database, that is, 175 to 2,003 in WoS, 89 to 1,981 in Scopus, and 126 to 3,492 when searched in Google Scholar. The highest number of articles (n = 10) related to dental caries were published in 2004. A total of 301 authors made valuable contributions to this field, out of which J.D. Featherstone had coauthored 6 articles. A significant negative correlation (p < 0.01) was found between the age of the article and the citation density (r =-0.545). However, a nonsignificant correlation (p = 0.952) occurred between the age of publication and the citation count (r = 0.006). CONCLUSION: The results of this systematic review provide a critical appraisal of the context underpinning scientific developments in the field of dental caries and also highlighted trends in clinical management and research.

Regulatory T Cells Restrain Pathogenic T Helper Cells during Skin Inflammation.

Psoriasis is a chronic relapsing, remitting interleukin (IL)-23/IL-17-driven skin disease mediated by the interplay of T cells and polymorphonuclear granulocytes. Although preclinical studies have provided insights into the mechanisms of disease initiation, the underpinnings of natural disease remission remain largely unknown. Here, we addressed the contribution of regulatory Foxp3+ T cells (Treg cells) in psoriasiform skin inflammation and remission using the Aldara-skin inflammation model in combination with the inducible depletion of Foxp3+ Treg cells. Loss of Treg cells exacerbated skin inflammation, but this did not involve increased γδ T cell expansion or the local production of the psoriasis-associated cytokines IL-17A, IL-17F, and IL-22, which are the main driving forces of disease development. Instead, Treg cells suppressed the infiltration of granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing CD4+ T cells into the lesioned skin, and neutralizing GM-CSF in Treg cell-deficient mice reversed hyper-inflammation, resulting in disease regression. Therefore, we identified a non-redundant role of Treg cells restraining skin inflammation and mediating skin homeostasis.

APOL1 risk allele RNA contributes to renal toxicity by activating protein kinase R.

APOL1 risk alleles associate with chronic kidney disease in African Americans, but the mechanisms remain to be fully understood. We show that APOL1 risk alleles activate protein kinase R (PKR) in cultured cells and transgenic mice. This effect is preserved when a premature stop codon is introduced to APOL1 risk alleles, suggesting that APOL1 RNA but not protein is required for the effect. Podocyte expression of APOL1 risk allele RNA, but not protein, in transgenic mice induces glomerular injury and proteinuria. Structural analysis of the APOL1 RNA shows that the risk variants possess secondary structure serving as a scaffold for tandem PKR binding and activation. These findings provide a mechanism by which APOL1 variants damage podocytes and suggest novel therapeutic strategies.

Histiocytosis - cutaneous manifestations of hematopoietic neoplasm and non-neoplastic histiocytic proliferations.

Histiocytoses are rare disorders characterized by the accumulation of cells derived from macrophages, dendritic cells or monocytes in various tissues. There is a broad spectrum of disease manifestations with some subtypes commonly showing skin lesions, while in others, the skin is rarely involved. Here, we describe cutaneous manifestations of histiocytoses belonging to the Langerhans group (L group), the group of cutaneous and mucocutaneous histiocytoses (C group) and the group of Rosai-Dorfman disease (RDD) and related histiocytoses (R group) according to the current classification. Characteristic clinical presentations noted were a rust-brown colour or xanthomatous aspect in many cases of histiocytoses. Histological criteria for differentiation are described. Immunohistochemistry shows positivity for S100 and CD1a in Langerhans-cell histiocytoses (LHCH) of the L group, while CD68 positivity with S100 and CD1a negativity are typical in histiocytoses of the C group of cutaneous and mucocutaneous histiocytoses. RDD in the R group shows positivity for S100 and CD68, while CD1a is negative. We further review the pathogenesis of LHCH based on insights on the central role of the mitogen-activated protein (MAPK) kinase pathway. Common mutations in various histiocytic populations of diverse ontogeny and at different stages of differentiation may be responsible for the diverse clinical picture of this neoplastic entity. For histiocytoses of the C group and R group, a reactive origin is discussed with the exception of the disseminated form of juvenile xanthogranuloma. We suggest exploring the role of an origin from skin residing histiocytes for the isolated cutaneous manifestation in some types. With regard to therapeutic options, skin-directed therapies are the first choice in limited disease, while systemic chemotherapy has traditionally been used in extensive disease. In Langerhans-cell histiocytoses and related entities, therapy by BRAF inhibition has led to a breakthrough especially in patients with an activation of the MAPK pathway.

More than 5000 patients with metastatic melanoma in Europe per year do not have access to recommended first-line innovative treatments.

BACKGROUND: Despite the efficacy of innovative treatments for metastatic melanoma, their high costs has led to disparities in cancer care among different European countries. We analysed the availability of these innovative therapies in Europe and estimated the number of patients without access to first-line recommended treatment per current guidelines of professional entities such as the European Society for Medical Oncology (ESMO), the European Organisation for Research and Treatment of Cancer (EORTC), the European Association of Dermato-Oncology (EADO), and European Dermatology Forum (EDF). MATERIALS AND METHODS: Web-based online survey was conducted in 30 European countries with questions about the treatment schedules from 1st May 2015 to 1st May 2016: number of metastatic melanoma patients, registration and reimbursement of innovative medicines (updated data, as of 1st October 2016), percentage of patients treated and availability of clinical studies and compassionate-use programmes. RESULTS: The recommended BRAF inhibitor (BRAFi) + MEK inhibitor (MEKi) combination was both registered and fully reimbursed in 9/30 (30%) countries, and in 13/30 (43%) (all from Eastern Europe) not reimbursed. First-line immunotherapy with anti-PD1 antibodies was registered and fully reimbursed in 14/30 (47%) countries, while in 13/30 (43%) (all from Eastern Europe) not reimbursed. It was estimated that in Europe 19,600 patients with metastatic melanoma are treated, and 5238 (27%) do not have access to recommended first-line therapy. Significant correlation was found between human development index (HDI, UNDP report 2015), (r = 0.662; p < 0.001), health expenditure per capita (r = 0.695; p < 0.001) and the Mackenbach score of health policy performance (r = 0.765; p < 0.001) with the percentage of patients treated with innovative medicines and a number of reimbursed medicines. CONCLUSIONS: Great discrepancy exists in metastatic melanoma treatment across Europe. It is crucial to increase the awareness of national and European policymakers, oncological societies, melanoma patients' associations and pharma industry.

Real-world approach to actinic keratosis management: practical treatment algorithm for office-based dermatology.

Actinic keratosis (AK) is a chronic skin disease in which multiple clinical and subclinical lesions co-exist across large areas of sun-exposed skin, resulting in field cancerisation. Lesions require treatment because of their potential to transform into invasive squamous cell carcinoma. This article aims to provide office-based dermatologists and general practitioners with simple guidance on AK treatment in daily clinical practice to supplement existing evidence-based guidelines. Novel aspects of the proposed treatment algorithm include differentiating patients according to whether they have isolated scattered lesions, lesions clustered in small areas or large affected fields without reference to specific absolute numbers of lesions. Recognising that complete lesion clearance is rarely achieved in real-life practice and that AK is a chronic disease, the suggested treatment goals are to reduce the number of lesions, to achieve long-term disease control and to prevent disease progression to invasive squamous cell carcinoma. In the clinical setting, physicians should select AK treatments based on local availability, and the presentation and needs of their patients. The proposed AK treatment algorithm is easy-to-use and has high practical relevance for real-life, office-based dermatology.